Angiopoietin-1 prevents hypertension and target organ damage through its interaction with endothelial Tie2 receptor

Abstract

AimsThe endothelium has emerged recently as a therapeutic target in the treatment of hypertension because endothelial dysfunction and subsequent vascular rarefaction cause target organ damage and further elevate blood pressure (BP). It led us to hypothesize that one of the endothelial survival factors, a potent derivative of angiopoietin-1 (cartilage oligomeric matrix protein, COMP-Ang-1), could be a novel class of antihypertensive agents that maintain endothelial integrity and function, thereby preventing the development of hypertension and target organ damage.Methods and resultsTo study the role of COMP-Ang-1 in preventing hypertension and target organ damage, a COMP-Ang-1 plasmid was electroporated into adductor muscles of 6 weeks old, pre-hypertensive, spontaneously hypertensive rats (SHRs), and the secretion of its expressed protein into the bloodstream was confirmed by western blotting. In comparison with sham and reporter gene transfer, COMP-Ang-1 gene transfer significantly prevented increases in systolic BP and reduced microvascular rarefaction and tissue damage in the heart and kidney. However, overexpression of soluble Tie2 receptor completely abolished these beneficial effects of COMP-Ang-1 gene transfer on SHRs, indicating that expressed COMP-Ang-1 protein has antihypertensive effects in SHRs by binding Tie2 receptors on the vascular endothelium. In particular, COMP-Ang-1 gene-transferred SHRs had significantly higher plasma levels of nitrite than other controls, which was found to be due to that expressed COMP-Ang-1 protein promoted nitrite synthesis by activating endothelial nitric oxide synthase, one of the Tie2 downstream-signalling molecules.ConclusionThe present study suggests a new potential of endothelial survival factor, COMP-Ang-1, as an antihypertensive agent that effectively reduces the hypertension-associated cardiovascular and renal damage, as well as prevents the further elevation of BP.

Angiogenesis and hypertension: an update

“…81 COMP-Ang-1 reduced microvascular rarefaction and tissue damage in the heart and the kidney and, intriguingly, also prevented the development of hypertension. These effects on systolic blood pressure disappeared when SHRs were pretreated with soluble Tie2 receptor, suggesting that the therapeutic effects of COMPAng-1 were mediated by the endothelium.…”

“…These effects on systolic blood pressure disappeared when SHRs were pretreated with soluble Tie2 receptor, suggesting that the therapeutic effects of COMPAng-1 were mediated by the endothelium. 81 Hypoxia served as the main trigger for angiogenesis, in a recent study, in SHRs. 82 Chronic normobaric hypoxia (10% O 2 ) decreased vascular resistance and, subsequently, systolic blood pressure by 26% already after 3 weeks when compared with normoxia (21% O 2 ).…”

Assessment of peripheral blood concentration of angiopoietin 1, angiopoietin 2 and Tie-2 (a tyrosine kinase receptor) of patients with goitre treated surgically

“…The stabilizing effect of angiopoietin 1 on the vessels was confirmed by the examination of COMP (cartilage oligomeric matrix protein) derived from the intestinal villi. Ang-1 prevents arterial hypertension and organ damage caused by high arterial pressure by the vascular anomalies alternation [29]. The study revealed considerably lower Ang-1 concentration, and higher concentration of Ang-2 in serum of patients with toxic goitre after the surgery, which appears to contradict the stabilizing function of Ang-2.…”

Arterial stiffness in hypertensives in relation to expression of angiopoietin-1 and 2 genes in peripheral monocytes

“…In addition, we cannot rule out the possibility that the increase in Angs could be compensatory and their action protective, since there are indications from some studies that they may reduce target organ damage in a hypertensive animal model. 27 A previous study by Sie et al 28 was the first that attempted to find a relation between arterial stiffness and angiogenic factors, and more specifically transforming growth factor. The study was not able to show any significant correlation.…”